Meta-Analysis of the Cardiovascular Outcomes with Dipeptidyl Peptidase 4 Inhibitors: Validation of the Current FDA Mandate

Earlier meta-analyses have demonstrated a significant reduction in major adverse cardiovascular events (MACE) with dipeptidyl peptidase 4-inhibitor (DPPI) use, as compared with placebo or alternative anti-diabetic therapies. However, the large phase III/IV trials, namely SAVOR-TIMI 53 and the EXAMINE trials, failed to demonstrate any significant differences in MACE between DPPI and placebo. We aimed to perform an updated meta-analysis of randomized controlled trials (RCTs) to investigate the differences in cardiovascular death, myocardial infarction (MI), and stroke between DPPI and placebo/alternative agents. We searched the MEDLINE, EMBASE, and Cochrane databases for relevant phase III/IV RCTs. Unpublished trials with results available on national clinical trials registers were also included. RCTs with follow-up duration a parts per thousand yen24 weeks were included if they compared DPPI with placebo or an alternative anti-diabetic agent. A total of 82 RCTs including 73,678 patients were included. We did not observe any significant difference in the pooled odds of cardiovascular death, MI, or stroke in the composite DPPI arm as compared with the control arm. Similarly, the pooled odds of all-cause death and MACE were statistically similar between the two groups. None of the clinical outcomes studied demonstrated evidence of statistical heterogeneity or publication bias. Due to a larger sample size and a longer duration of follow-up, both SAVOR-TIMI 53 and EXAMINE trials had a considerably larger contribution to the pooled estimates in our meta-analysis, driving the updated pooled estimates towards null for all clinical outcomes assessed. DPPI use was not associated with increased incidence of cardiovascular mortality, MI, stroke, or MACE compared with placebo or alternative anti-diabetic agents.